The focus of this research is to define the natural history of HPVinfection and cervical neoplasia, particularly immunologic and other cofactors that explain why cervical HPV infection (a common sexually-transmitted diseases) progresses in rare instances to high-grade neoplasia. Accompanying prevention research on HPV diagnostics attempts to improve cervical cancer screening, while projects on HPV immunology are on the forefront of worldwide etiologic and preventive vaccine development efforts. Several methodologic and long-term projects were completed in FY 2000. Extreme associations(relative risks approx. 500) of high-grade cervical intraepithelial neoplasia were associated with infection with cancer-associated HPV types, based on data from the Costa Rican cohort study. Improved cytologic and HPV DNA test methods were validated during the enrollment phase of the Costa Rican cohort, a 10,000-womanrandom sample of a high-risk province of Costa Rica. Much of the natural history work in the next few years will derive from the follow-up data from this cohort. Serologic projects continue to demonstrate the HPV-type specificity of the new tests based on synthesized virus-like particles now available for major cancer-associated types. Methods research continues on biomarkers of possible protective immunity to HPV infection that might be useful for the proposed Phase 3 prophylactic trial against HPV 16 infection.Prophylactic vaccination against HPV 16, the most important HPV type,is the central and most ambitious aspect of this project. The immunogenicity and safety of HPV 16 virus-like particles as antigens are being evaluated in collaborative Phase 1 and 2 trials at Johns Hopkins. Results to date are very promising. A full-scale Phase 3 randomized controlled trial of two candidate vaccines against placebo is tentatively scheduled to begin next year if the studies among U.S. women continue as hoped. Costa Rica was chosen for the Phase 3 trial because of our extensive successful scientific collaborations there, the continued high risk of cervical cancer,the universal medical system providing national linkage, and the likelihood of very high participation over many necessary years of close clinical follow-up. Over 10,000 women are scheduled to be vaccinated.Other NCI CollaboratorsJay Berzofsky, M.D.Diane Solomon, M.D.Douglas Lowy, M.D.John Schiller, M.D.Other Scientific CollaboratorsConcepcion Bratti, M.D., Costa Rican Social SecurityRobert Burk, M.D., Albert Einstein College of MedicineThomas Cox, M.D., University of California, Santa BarbaraAndrew Glass, M.D., Portland Kaiser-PermanentePatti Gravitt, M.S., Johns Hopkins University Rolando Herrero, M.D., International Agency for Cancer Research Sharon Hillier, Ph.D., University of Pittsburgh Martha Hutchinson, M.D., Brown UniversityKai-Li Liaw, Ph.D., University of Pittsburgh Attila Lorincz, Ph.D., Digene Corporation Ana Cecilia Rodriguez, M.D., Costa Rican Social Security David Scott, M.D., Portland Kaiser Permanente Howard Strickler, M.D., M.P.H., Albert Einstein College of Medicine David Zahniser, Ph.D., Cytyc Corporation